The dopaminergic basis of human behaviors: A review of molecular imaging studies

Abstract

This systematic review describes human molecular imaging studies which have investigated alterations in extracellular DA levels during performance of behavioral tasks. Whilst heterogeneity in experimental methods limits meta-analysis, we describe the advantages and limitations of different methodological approaches. Interpretation of experimental results may be limited by regional cerebral blood flow (rCBF) changes, head movement and choice of control conditions. We revisit our original study of striatal DA release during video-game playing [Koepp, M.J., Gunn, R.N., Lawrence, A.D., Cunningham, V.J., Dagher, A., Jones, T., Brooks, D.J., Bench, C.J., Grasby, P.M., 1998. Evidence for striatal dopamine release during a video game. Nature 393, 266–268] to illustrate the potentially confounding influences of head movement and alterations in rCBF. Changes in [¹¹C]raclopride binding may be detected in extrastriatal as well as striatal brain regions—however we review evidence which suggests that extrastriatal changes may not be clearly interpreted in terms of DA release. Whilst several investigations have detected increases in striatal extracellular DA concentrations during task components such as motor learning and execution, reward-related processes, stress and cognitive performance, the presence of potentially biasing factors should be carefully considered (and, where possible, accounted for) when designing and interpreting future studies.

Introduction

In 1998, we reported increased dopamine (DA) release in man during performance of a behavioral task (Koepp et al., 1998) using positron emission tomography (PET). In the presence of the DA D_2/3 receptor radiotracer [¹¹C]raclopride, volunteers played a videogame in which a tank had to be successfully steered around a battlefield arena to collect flags and obtain a monetary reward. Decreased [¹¹C]raclopride binding, consistent with increased DA release, was observed in the striatum of subjects whilst playing the videogame in comparison to a rest condition. This study demonstrated DA release during normal human behavior for the first time, and set the stage for non-invasive investigation of the role of DA in processes such as learning, reward and sensorimotor integration. As will be reviewed here, literature describing the dopaminergic basis of human behavior is now rapidly expanding and DA release has been specifically associated with several motor, reward-related and cognitive functions. In parallel, the past decade has seen much refinement and evolution of methodological approaches to measuring DA release using D_2/3 radiotracers using PET and the related technique, single photon emission tomography (SPET).

From a historical perspective, suggestions that select DA receptor radiotracers may be used to image changes in extracellular DA levels began in 1989, with publication of ex vivo data demonstrating the sensitivity of D_2/3 receptor radiotracers to changes in endogenous DA levels (Ross and Jackson, 1989a, Ross and Jackson, 1989b, Seeman et al., 1989). Indications that this sensitivity could also be observed in vivo using positron emission tomography (PET) technology rapidly followed, when increased displacement of the D_2/3 tracer (¹⁸F)-N-methylspiroperidol was observed following administration of the anticholinergic benztropine to baboons (Dewey et al., 1990). This finding was subsequently confirmed by applying the same technique to investigate amphetamine-induced DA release (Dewey et al., 1991). Landmark investigations in humans followed swiftly afterwards; data showing decreases in binding of the D_2/3 receptor PET radiotracer [¹¹C]raclopride in response to administration of amphetamine were published in 1992 (Farde et al., 1992) and similar results were subsequently obtained following administration of the DA re-uptake inhibitor methylphenidate (Volkow et al., 1994).

The ability of D_2/3 receptor radiotracers to index DA release in vivo is commonly described by the ‘classical occupancy model’; D_2/3 receptor radiotracers compete with DA for receptor binding, thus a decrease in radiotracer binding potential (BP) is interpreted as an increase in DA release (see Laruelle, 2000a). The amount of radiotracer present in a particular brain region of interest (ROI) can be detected using PET and SPET. The specific binding of the radiotracer to receptors is then inferred through careful modeling of radiotracer kinetics. These techniques, used in combination with administration of pharmacological compounds that target non-dopaminergic neurotransmitter systems, have allowed examination of the neuropharmacology of DA release in the human brain (Breier et al., 1998, Brody et al., 2004, Dewey et al., 1993, Vollenweider et al., 1999), and studies employing pharmacological challenges which release DA (e.g. amphetamine), reveal much about the neurochemistry of many brain disorders (Abi-Dargham et al., 1998, Breier et al., 1997, Laruelle et al., 1996, Laruelle et al., 1999, Piccini et al., 2003, Rosa et al., 2002, Singer et al., 2002, Volkow et al., 1997, Volkow et al., 2007). However, the ability to study DA release produced by ethologically relevant, non-pharmacological stimuli is of greater functional relevance in terms of investigating the dopaminergic basis of human behavior and its role in disease mechanisms.

The possibility that D_2/3 radiotracer PET techniques might prove sensitive enough to measure the relatively smaller changes in DA release expected following non-pharmacological interventions was first proposed in 1995 following detailed review of dopaminergic neurophysiology and integration of these parameters into simulations (Fischer et al., 1995, Morris et al., 1995). Encouraged by the positive results of these simulations, we performed our initial study of DA release during videogame playing and observed significant decreases in [¹¹C]raclopride BP (Koepp et al., 1998).

Since the publication of our original finding (Koepp et al., 1998), there have been a large number of studies in this field, employing a number of different approaches, and there is no clear consensus as to the best method. The aim of this paper is to systematically review the molecular imaging studies of DA release in man and to critically appraise the methodological approaches used. In addition, we re-analyze our original data to evaluate and illustrate the degree to which certain methodological factors may alter findings. We conclude by reviewing the findings of molecular imaging studies of non-pharmacologically evoked changes in DA release in man, and summarize what these studies have told us about the role of DA in aspects of human behavior.

As studies in experimental animals have since significantly increased our understanding of dopaminergic neurophysiology, we begin this review by describing components of this system relevant to measuring non-pharmacologically induced changes in DA release using D_2/3 receptor radiotracers and PET methodology. We then present the findings of our systematic review and re-evaluation of previous data.